Gene Changes ID Resistant Prostate Cancer

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Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Note that this genetic analysis of prostate cancer samples demonstrated that mutations in certain "common fragile sites" confer a high risk of downstream treatment failure, likely due to an increase in genome-wide mutation frequency.

Any alteration in a genetically unstable region of prostate cancer cells significantly increased the odds of treatment failure, according to a preliminary study that suggests the potential for a test to identify treatment-resistant disease.

Treatment failure within 5 years occurred in 36% of intermediate-risk patients with alterations in common fragile sites (CFSs) versus 10% in similar patients with no CFS alterations.

"We found that changes in even one of these hot spots would make the whole genome unstable and cause further genetic changes," Fotouhi Ghiam said during a press briefing.

"The results of this study should be validated in other cohorts treated with radiotherapy or surgery at other centers," he added. "If the results are upheld, we can develop a new genetic test based on genetic changes in this area."

The findings add another piece to a puzzle that has stumped prostate cancer researchers and clinicians for years: why one of every three men with intermediate-risk prostate cancer progresses to biochemical failure, despite having characteristics similar to the other two who have durable treatment responses.

Investigators had suspected the explanation involved genetic changes in tumor cells, but until recently, few clues emerged regarding the genomic location of the changes. Studies eventually led to CFSs, sites with the tumor's chromosomal makeup that are particularly sensitive to DNA damage.

On the basis of previous research, investigators had reason to believe that alterations in CFSs might adversely affect treatment outcomes. To investigate the possibility, Fotouhi Ghiam and colleagues examined 13 previously characterized CFSs, focusing on gene copy number alterations (CNAs).

The study involved archived biopsy specimens from 124 men with intermediate-risk prostate cancer treated with definitive radiation therapy. The cohort had a median follow-up of almost 8 years.

Overall, a majority of the patients had one or more CNAs in CFSs, which was significantly associated with increased genomic instability, reflected in a higher percent genome alteration (P<0.0001). Allelic gains and losses occurred most often in four of the 13 CFSs and were associated with increased genomic instability.

Fotouhi Ghiam reported that 55 patients progressed to biochemical relapse during follow-up. By univariate analysis, a CNA in one or more CFSs doubled the likelihood of biochemical failure (HR 2.13, 95% CI 1.17-3.86, P=0.011). Multivariate analysis showed that even a single CNA in a CFS significantly increased the risk of biochemical relapse (HR 2.94, 95% CI 1.51-5.75, P=0.0016).

If additional studies corroborate the results, a test could be developed to identify which patients are likely to have treatment-resistant disease. Those patients might be considered candidates for more aggressive treatment, such as multimodality regimens.

The study illustrates the potential of personalized medicine to make a difference at the level of the individual patient, said ASTRO president Colleen Lawton, MD, of the Medical College of Wisconsin in Milwaukee.

"We like simplicity and simple analyses of low-, intermediate-, and high-risk disease, but the reality is that cancer is not that simple," she said. "When we start to come down to the individual level, these types of personalized-medicine questions are the next step we need to take to understand whether, in that bucket of intermediate disease, there is a way to subdivide it so that we give the right treatment to the right patient."

Fotouhi Ghiam and co-investigators reported no relevant disclosures.

Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner